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WO2011151652A1 - Composés de benzodiazépine utiles pour le traitement de l'hépatite c - Google Patents

Composés de benzodiazépine utiles pour le traitement de l'hépatite c Download PDF

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Publication number
WO2011151652A1
WO2011151652A1 PCT/GB2011/051048 GB2011051048W WO2011151652A1 WO 2011151652 A1 WO2011151652 A1 WO 2011151652A1 GB 2011051048 W GB2011051048 W GB 2011051048W WO 2011151652 A1 WO2011151652 A1 WO 2011151652A1
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Prior art keywords
alkyl
formula
pharmaceutically acceptable
compound
halogeno
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Inventor
Michael Christopher Stratton Barnes
Stephen Sean Flack
Ian Fraser
James Andrew Lumley
Pui Shan Pang
Keith Charles Spencer
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Arrow Therapeutics Ltd
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Arrow Therapeutics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton

Definitions

  • the present invention relates to a series of benzodiazepine derivatives and, in particular, it relates to a series of benzodiazepine derivatives which are inhibitors of the hepatitis C virus (HCV) Polymerase enzyme and are therefore active against HCV infection.
  • This invention also relates to methods for the preparation of such benzodiazepine derivatives and novel intermediates in the preparation thereof, to pharmaceutical compositions containing such benzodiazepine derivatives, to the use of such benzodiazepine derivatives in the preparation of medicines and to the use of such benzodiazepine derivatives in the treatment of HCV infection.
  • Hepatitis C virus is a member of the Flaviviridae family of viruses and HCV infection is the leading cause of chronic liver disease worldwide. An estimated 170 million people are infected with HCV worldwide. Following the initial acute infection, a majority of infected individuals develop chronic hepatitis, which can progress to liver fibrosis, cirrhosis, end-stage liver disease and hepatocellular carcinoma. Liver cirrhosis due to HCV infection is the principal cause of liver transplantation.
  • HCV has a positive-sense, single- stranded R A genome that encodes a single polyproptein which undergoes posttranslational cleavage to provide ten viral proteins, including viral structural proteins (envelope
  • glycoproteins El and E2 glycoproteins El and E2, and the core nucleocapsid protein), non-structural proteins (helicase, polymerase and protease) and other proteins of unknown function. Replication of the viral genome is mediated by the RNA-dependent RNA polymerase.
  • WO 07/034127 discloses a series of benzodiazepine derivatives that are inhibitors of the HCV polymerase.
  • HCV polymerase inhibitors which differ by virtue of their chemical structure and may have superior potency against HCV Polymerase and/or advantageous physical properties and/or favourable toxicity profiles and/or favourable metabolic profiles in comparison with other known HCV Polymerase inhibitors.
  • L 1 represents O or NR 10 , wherein R 10 represents hydrogen, (l-6C)alkyl, acetyl,
  • L represents -(CR R ) n -, wherein n represents 1 , 2, 3, 4 ,5 or 6 and R and R
  • X represents CH or N
  • R 1 represents hydrogen or fluoro
  • R represents hydrogen, halogeno, (l-6C)alkyl, (l-6C)alkoxy, formyl, (2-6C)alkanoyl, trifluoromethyl or trifluoromethoxy;
  • R represents hydrogen, (l-6C)alkyl or halogeno
  • R 4 represents hydrogen, halogeno, (l-6C)alkyl, (l-6C)alkoxy, halogeno-(l-6C)alkyl, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (2-6C)alkanoyl, or -(CH 2 )p-NR 13 R 14 , wherein p represents 0, 1 or 2 and R 13 and R 14 independently represent hydrogen or (1 -3C)alkyl, or R and R are joined so as to form a 4, 5, 6 or 7 membered heterocyclic ring which optionally comprises, in addition to the nitrogen atom to which R 13 and R 14 are attached, 1 or 2 further heteroatoms independently selected from O, N or S, and wherein said heterocyclic ring is optionally substituted with 1 , 2 or 3 substituents
  • R 5 represents hydrogen, (l-6C)alkyl or halogeno
  • R 6 represents hydrogen, halogeno, (l-6C)alkyl, (l-6C)alkoxy, halogeno-(l-6C)alkyl or halogeno-(l-6C)alkoxy;
  • R 7 represents hydrogen, (l-6C)alkyl, (l-6C)alkoxy, halogeno, trifluoromethyl or
  • R represents hydrogen, (l-6C)alkyl, (3-7C)cycloalkyl, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, aryl, a 5 or 6 membered monocyclic heteroaryl ring which comprises 1, 2, 3 or 4 ring heteroatoms independently selected from O, N or S, or a 9 or 10 membered bicyclic heteroaryl ring which comprises 1, 2, 3, 4 or 5 ring heteroatoms independently selected from O, N or S, wherein said aryl, monocyclic heteroaryl or bicyclic heteroaryl ring is optionally substituted with 1, 2 or 3 substituents independently selected from R 15 ;
  • R 9 represents hydrogen, (l-6C)alkyl, (3-7C)cycloalkyl, (l-6C)alkylthio, (l-6C)alkylsulfinyl or (l-6C)alkylsulfonyl,
  • R 15 represents halogeno, (l-6C)alkyl, (l-6C)alkoxy, halogeno-(l-6C)alkyl, halogeno-(l- 6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (2-6C)alkanoyl, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, sulfamoyl, N-(l-6C)alkylsulfamoyl, N-(l-6C)alkylsulfamoyl
  • q represents 0, 1, 2, 3 or 4 and R and R independently represent hydrogen, (l-6C)alkyl or cyclopropyl, or R 16 and R 17 are joined so as to form a 4, 5, 6 or 7 membered heterocyclic ring which optionally comprises, in addition to the nitrogen atom to which R and R are attached, 1 or 2 further heteroatoms independently selected from O, N or S.
  • halogeno is used herein to denote fluoro, chloro, bromo and iodo.
  • (l-6C)alkyl is intended to mean a saturated carbon chain of 1 to 6 carbon atoms in length which may be straight-chained or branched.
  • references to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched-chain alkyl groups such as tert-butyl are specific for the branched chain version only.
  • “(l-6C)alkyl” includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, tert-pentyl, hexyl and isohexyl.
  • the terms "(l-3C)alkyl” and (l-2C)alkyl” are to be construed accordingly.
  • (1-6C) alkoxy is intended to mean a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched, linked to oxygen.
  • “(1-6C) alkoxy” includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy and hexoxy.
  • (l-6C)alkoxy-(l-6C)alkyl is intended to mean a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched, linked via oxygen to another saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight- chained or branched.
  • “(l-6C)alkoxy-(l-6C)alkyl” includes, but is not limited to, methoxyethyl, methoxypropyl, ethoxypropyl, propoxyethyl and butoxypropyl.
  • (2-6C)alkanoyl is intended to mean a saturated carbon chain of 1 to 5 carbon atoms in length, which may be straight-chained or branched, linked to carbonyl.
  • “(2-6C)alkanoyl” includes acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl and hexanoyl.
  • (l-6C)alkylsulfonyl is intended to mean a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched, linked to sulfur dioxide.
  • “(l-6C)alkylsulfonyl” includes, but is not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert- butylsulfonyl, pentylsulfonyl and hexylsulfonyl.
  • (l-6C)alkylsulfmyl is intended to mean a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched, linked to sulfur oxide.
  • (l-6C)alkylsulfinyl includes, but is not limited to, methylsulfmyl, ethylsulfmyl, propylsulfmyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfmyl, tert- butylsulfmyl, pentylsulfmyl and hexylsulfinyl.
  • (l-6C)alkylthio is intended to mean a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched, linked to sulfur.
  • (l-6C)alkylsulfmyl includes, but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio and hexylthio.
  • halogeno-(l-6C)alkyl is intended to mean a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched, wherein at least one of the hydrogen atoms has been replaced by a halogeno atom.
  • halogeno-(l- 6C)alkyl includes, but is not limited to, difluoromethyl, trifluoromethyl,
  • halogeno-(l-6C)alkoxy is intended to mean a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched, wherein at least one of the hydrogen atoms has been replaced by a halogeno atom, linked to oxygen.
  • halogeno-(l-6C)alkoxy includes, but is not limited to, difluoromethoxy, trifluoromethoxy, chloro(difluoro)methoxy, difluoroethoxy and difluoropropoxy.
  • hydroxy-(l-6C)alkyl is intended to mean a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched, wherein at least one of the hydrogen atoms has been replaced by a hydroxy group.
  • hydroxy-(l- 6C)alkyl includes, but is not limited to, hydroxymethyl, dihydroxyethyl and
  • a sulfamoyl group is a group H2N-SO2-.
  • N-(l-6C)alkylsulfamoyl is intended to mean a sulfamoyl group wherein one of the hydrogen atoms of the amino group has been replaced by a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched.
  • N-(l-6C)alkylsulfamoyl includes, but is not limited to, methylaminosulfonyl
  • N,N-di(l-6C)alkylsulfamoyl is intended to mean a sulfamoyl group wherein both of the hydrogen atoms of the amino group have been replaced by a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched.
  • N,N-di[(l-6C)alkyl]sulfamoyl includes, but is not limited to,
  • a "(l-6C)alkylsulfonylamino” group is a group (l-6C)alkyl-S(0)2-N(H)-, wherein the (l-6C)alkyl group is a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched.
  • “(l-6C)alkylsulfonylamino” includes, but is not limited to, mesylamino, ethylsulfonylamino and isopropylsulfonylamino.
  • a "(l-6C)alkylsulfonyl-N-(l-6C)alkylamino” group is a group (l-6C)alkyl-S(0) 2 - [N(l-6C)alkyl]-, wherein each (l-6C)alkyl group is independently a saturated carbon chain of 1 to 6 carbon atoms in length, which may be straight-chained or branched.
  • N- (l-6C)alkyl-(l-6C)alkylsulfonylamino” includes, but is not limited to,
  • aryl is intended to mean phenyl or naphthyl.
  • the term "5 or 6 membered monocyclic heteroaryl ring” is intended to mean a 5 or 6 membered, totally unsaturated and/or aromatic monocyclic ring which comprises 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is possible, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring.
  • Examples of 5 or 6 membered monocyclic heteroaryl rings include, but are not limited to, pyrrolyl, furanyl, imidazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyridinyl, pyrrolyl, isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, 1,2,4-triazolyl and thiophenyl.
  • 9 or 10 membered bicyclic heteroaryl ring is intended to mean a 9 or 10 membered, totally unsaturated and/or aromatic bicyclic ring which comprises 1, 2, 3, 4 or 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is possible.
  • 9 or 10 membered bicyclic heteroaryl rings include, but are not limited to, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl.
  • (3-7C)cycloalkyl is intended to mean a saturated carbon 3 to 7 membered ring.
  • (3-7C)cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.
  • R 8 and R 9 to R 13 and R 14 or to R 16 and R 17 joining so as to form a 4, 5, 6 or 7 membered heterocyclic ring which optionally comprises, in addition to the nitrogen atom to which they are attached, 1 or 2 one or more additional heteroatoms independently selected from O, N or S
  • the ring so formed suitably contains 1 or 2 additional heteroatoms and, more suitably contains 1 additional heteroatom, representative examples of which are listed above.
  • the ring so formed may be selected from azetidin-l-yl, pyrrolidin-l-yl, pyrazolidin-l-yl, piperidin-l-yl, morpholin-4-yl and piperazin- 1-yl.
  • optically active or racemic forms by virtue of the asymmetric carbon atom
  • the invention includes in its definition any such optically active or racemic form which possesses the property of HCV Polymerase inhibitory activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Racemic compounds and racemic intermediates thereof are drawn herein as flat structures whereas stereospecific compounds and stereospecific intermediates thereof are drawn with the appropriate stereochemistry indicated.
  • L 1 represents O or NR 10 , wherein R 10 represents hydrogen or (l-6C)alkyl, particularly wherein R 10 represents hydrogen or (l-2C)alkyl.
  • L 1 represents O.
  • L represents -(CR R ) n -, wherein n represents 1 , 2 or 3 (particularly wherein n represents 1), and R 11 and R 12 independently represent hydrogen or (l-2C)alkyl.
  • L may represent -CH 2 -.
  • R 1 represents hydrogen
  • R represents halogeno,particularly fluoro.
  • R represents hydrogen
  • R 4 represents halogeno or (l-6C)alkoxy, particularly halogeno or (l-2C)alkoxy.
  • R 4 may represent chloro, methoxy or ethoxy.
  • R 5 represents hydrogen.
  • R 6 represents halogeno, for example chloro.
  • R 7 represents hydrogen
  • R represents hydrogen, (l-6C)alkyl or (3-7C)cycloalkyl.
  • R 9 represents hydrogen, (l-6C)alkyl or (3-7C)cycloalkyl.
  • R 1 and R3 are both hydrogen and R 2 represents halogeno (particularly fluoro).
  • R 5 and R 7 are both hydrogen
  • R 4 represents halogeno, (l-6C)alkyl, (l-6C)alkoxy, halogeno-(l-6C)alkyl, halogeno-(l-6C)alkoxy, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (2-6C)alkanoyl or -(CH 2 ) P -NR 13 R 14 , wherein p represents 0, 1 or 2 and R 13 and R 14 independently represent hydrogen or (1 - 3C)alkyl, or R 13 and R 14 are joined so as to form a 4, 5, 6 or 7 membered heterocyclic ring which optionally comprises, in addition to the nitrogen atom to which R 13 and R 14 are attached, 1 or 2 further heteroatoms independently selected from O, N or S, and wherein said heterocyclic ring is optionally substituted with 1, 2 or 3 substituents selected from R 15 as herein defined; and R
  • R 5 and R 7 are both hydrogen, R 4 represents halogeno, or (l-6C)alkoxy; and R 6 represents halogeno (particularly chloro).
  • R 1 , R 3 , R 5 and R 7 are all hydrogen; R 2 represents halogeno (particularly fluoro); R 4 represents halogeno or (l-6C)alkoxy; and R 6 represents halogeno (particularly chloro).
  • the compound of Formula (I) has the configuration shown in Formula (IA):
  • L 1 , L 2 , X, R 2 , R 4 R 5 , R 6 , R 7 , R 8 and R 9 are as hereinbefore defined.
  • R 1 and R 3 as shown in the Formula (I) are both hydrogen.
  • the compound of Formula (I) has the configuration shown in Formula (IB):
  • L 1 , L 2 , X, R 2 , R 4 , R 6 , R 8 and R 9 are as hereinbefore defined.
  • R 1 , R3 , R 5 and R 7 as shown in the Formula (I) are all hydrogen.
  • Reference herein to a compound of Formula (I) should be understood to refer equally to a compound of Formula (I), (IA) or (IB).
  • Particular novel compounds of Formula (I) include, but are not limited to, the following compounds:
  • novel compounds of Formula (I) include, but are not limited to, the following compounds:
  • a particular novel compound of Formula (I) is 2-(2-amino-2-oxoethoxy)-N-(5-(2,4- dichloro-6-ethoxyphenyl)-2-oxo-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)-5- fluoronicotinamide and pharmaceutically acceptable salts thereof.
  • a particular novel compound of Formula (I) is (S)-2-(2-amino-2-oxoethoxy)-N-(5- (2,4-dichloro-6-ethoxyphenyl)-2-oxo-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)-5- fluoronicotinamide and pharmaceutically acceptable salts thereof.
  • a suitable pharmaceutically acceptable salt of a compound of Formula (I) is, for example, where the compound is sufficiently basic, an acid addition salt such as a
  • hydrochloride hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or /?-toluenesulfonate salt.
  • anion There may be more than one anion depending on the number of charged functions and the valency of the anions.
  • Other pharmaceutically acceptable salts, as well as pro-drugs such as pharmaceutically acceptable esters and pharmaceutically acceptable amides may be prepared using conventional methods.
  • the compounds of the invention may be administered in the form of a pro-drug, that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • pro-drugs include in vivo cleavable amide derivatives that may be formed at an amino group in a compound of Formula (I).
  • the present invention includes those compounds of Formula (I) as hereinbefore defined when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of Formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of Formula (I) may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable pro-drug of a compound of Formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • a suitable pharmaceutically acceptable pro-drug of a compound of Formula (I) that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C 2-10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • the in vivo effects of a compound of Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of Formula (I). As stated hereinbefore, the in vivo effects of a compound of Formula (I) may also be exerted by way of metabolism of a precursor compound (a pro -drug).
  • Lg represents a suitable leaving group and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , L 2 and X are as defined for Formula (I), except that any functional group is protected if necessary;
  • a compound of Formula (II) may be reacted with a compound of Formula (III) in the presence of a suitable coupling agent, for example 0-(lH-benzotriazol-l- yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate (HBTU), optionally in the presence of a suitable base, for example triethylamine (TEA), a suitable solvent, for example N,N- dimethylformamide (DMF), and at a suitable temperature, for example room temperature.
  • a suitable coupling agent for example 0-(lH-benzotriazol-l- yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate (HBTU)
  • a suitable base for example triethylamine (TEA)
  • a suitable solvent for example N,N- dimethylformamide (DMF)
  • reactive derivative of the compound of the Formula (III) is meant a carboxylic acid derivative that will react with the compound of Formula (II) to give the corresponding amide.
  • a suitable reactive derivative of a compound of the Formula (III) would be readily determined by persons skilled in the art.
  • the reactive derivative may be an acyl halide, for example an acyl chloride formed by the reaction of the compound of Formula (III) and an inorganic acid chloride, for example thionyl chloride.
  • a compound of Formula (IV) wherein Lg represents a suitable leaving group, for example fluoro, chloro, bromo, iodo, mesylate or tosylate may be reacted with an amine of Formula (V) in a suitable solvent, for example a 4:1 mixture of 1,4-dioxane in water, by heating to a suitable temperature, for example 100 to 200°C, more suitably about 160°C, using a suitable heat source, for example microwave radiation.
  • a suitable solvent for example a 4:1 mixture of 1,4-dioxane in water
  • compounds of Formula (II) may be prepared by reacting a compound of Formula (VI) with a compound of Formula (VII) in the presence of silver and a suitable catalyst wherein Pi and P 2 represent suitable protecting groups:
  • R 4 , R 5 , R 6 and R 7 are as defined for Formula (I), except that any functional group is protected if necessary, and thereafter removing the protecting groups (i.e. including Pi and P 2 ).
  • a compound of Formula (VI) wherein Pi and P 2 represent suitable protecting groups, for example p-methoxybenzyl (PMB) and tert-butyloxycarbonyl respectively, may be reacted with a compound of Formula (VII) in a suitable solvent, for example THF, in the presence of silver, for example Ag 2 C0 3 , a suitable catalyst, for example
  • tetrakis(triphenylphosphine)palladium(0) and optionally in the presence of a suitable base, for example K 2 C0 3 , by heating to a suitable temperature, for example reflux temperature.
  • a suitable base for example K 2 C0 3
  • a process for the preparation of compounds of Formula (I) may comprise converting a compound of Formula (I) into another compound of Formula (I) using standard chemical reactions well-known to those skilled in the art to produce another compound of the invention.
  • Chemical conversions of this type are well known to those skilled in the art and may include functional group interconversions such as hydrolysis, hydrogenation, hydrogenolysis, oxidation or reduction, and/or further functionalisation by standard reactions such as amide or metal-catalysed coupling, or nucleophilic displacement reactions. Examples of such conversions are described, for instance, in Comprehensive Organic Chemistry, Volume 2, p3, D. Barton and D. Ollis Eds, Pergamon, 1979, Comprehensive Functional Group
  • Any protecting groups utilised in the processes described herein may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods.
  • Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • a suitable protecting group for the ring nitrogen of the benzodiazepine would be p-methoxybenzyl.
  • the p-methoxybenzyl can be removed, for example by treating with aluminium trichloride or cerium(IV) ammonium nitrate.
  • a process for the manufacture of compounds of Formula (I) in the form of a single enantiomer may comprise separating a racemic compound of the invention into separate enantiomers.
  • suitable methods for separating the enantiomers of a racemic compound include chromatography using a suitable chiral stationary phase; or conversion of a racemic mixture into diastereomeric derivatives, separation of the mixture of diastereomeric derivatives into two single diastereomers, and regeneration of a separate single enantiomer from each separate single diastereomer; or selective chemical reaction of one of the enantiomers of a racemic compound (kinetic resolution) using a diastereoselective reaction catalysed by a microbiological agent or an enzyme.
  • compounds of the invention in the form of a single enantiomer may be prepared by using chiral starting materials to carry out one of the processes described above.
  • compounds of the invention in the form of a single enantiomer may be prepared by using a dynamic kinetic resolution method, such as the method described herein.
  • Recombinant HCV polymerase (BK strain) was expressed and purified from E. coli with a 21 amino acid C-terminal deletion and a His 6 -tag.
  • the general assay buffer consisted of 20 mM Tris (pH 7.5), 25 mM KC1, 5 mM MgCl 2 , 3 mM DTT, 0.5 mg/ml BSA, 0.01%
  • Tween20 The standard reaction, in 96 well plates, contained 10 ⁇ of diluted compound, 50 ⁇ of substrate and 40 ⁇ of enzyme. Compounds, supplied as 10 mM stocks in DMSO, were diluted initially in neat DMSO, and subsequently buffer was added to give a DMSO concentration of 30%; 10 ⁇ of this was added to the assay plate to give a final concentration in the 100 ⁇ assay of 3% DMSO.
  • the biotinylated Ui 3 :PolyA RNA substrate was pre- annealed with 40 ⁇ 5 ' -biotinylated U 13 (Dharmacon) and 213 ⁇ g/ml PolyA (Amersham Biosciences) in water incubated at 70°C for 5 minutes before being cooled on ice.
  • Substrate (50 ⁇ ) was added in buffer to give a final concentration in the 100 ⁇ assay of 125 nM biotinylated Ui 3 :0.63 ⁇ PolyA and 200 nM UTP with 0.4 ⁇ [ 33 P]-UTP per well (Perkin Elmer).
  • the reaction was initiated by the addition of 40 ⁇ of enzyme in buffer to give 100 nM final concentration.
  • the reaction was incubated at 25°C for 100 minutes and then stopped by addition of 100 ⁇ of 100 mM EDTA.
  • the samples were then transferred to 96 well Streptavidin-coated FlashPlates (Perkin Elmer) and incubated at room temperature for ⁇ 1 hour to allow binding to occur.
  • the plates were then washed three times with phosphate- buffered saline containing 0.05% Tween20 in an automated plate washer to remove unincorporated [ 33 P]-UTP, and then counted in a Packard TopCount Scintillation Counter.
  • Each plate included a set of positive controls (no compound, maximum signal) and negative controls (no enzyme, minimum signal) and in each run at least one reference compound was included to validate the assay.
  • the IC 50 concentration required to inhibit the enzyme activity by 50%, was calculated using an 8-point IC 5 o curve and fitted using the program XLfit (IDBS).
  • HCV replicon cells Huh 9B (ReBlikon), containing the firefly luciferase - ubiquitin - neomycin phosphotransferase fusion protein and EMCV-IRES driven HCV polyprotein with cell culture adaptive mutations.
  • the culture medium consisted of DMEM with 4500g/l glucose and glutamax (Gibco 61965-026) supplemented with 1 x non-essential amino acids (Invitrogen 11140-035), penicillin (100 IU/ml) / streptomycin (100 ⁇ ) (Invitrogen 15140-122), FCS (10%, 50ml) and 1 mg/ml G418 (Invitrogen 10131-027) & 10 % Australian foetal calf serum (Invitrogen 10099-141).
  • a flask of cells was trypsinised and a cell count carried out.
  • Cells were diluted to 100,000 cells/ml and 100 ⁇ of this used to seed one opaque white 96-well plate (for the replicon assay) and one flat-bottomed clear plate (for the tox assay) for every five compounds to be tested for IC 50 .
  • Wells G12 and H12 were left empty in the clear plate as the blank. Plates were then incubated at 37°C in a 5% C0 2 environment for 24 h.
  • the cells in the white plate were harvested by washing in PBS ( ⁇ per well) and gently tapping dry before addition of 20 ⁇ , per well of lysis buffer (25mM tris-phosphate, 8mM MgCl 2 , ImM DTT, 1% Triton X-100, 15% glycerol. pH to 7.8 using KH 2 P0 4 prior to triton and glycerol addition.
  • lysis buffer 25mM tris-phosphate, 8mM MgCl 2 , ImM DTT, 1% Triton X-100, 15% glycerol. pH to 7.8 using KH 2 P0 4 prior to triton and glycerol addition.
  • the M injector of the microplate luminometer (Lmax, Molecular Devices) was primed with 5 x 300 ⁇ injections of the diluted substrate. After 5-60 min incubation in lysis buffer at room temperature, a plate was inserted into the luminometer and 100 ⁇ luciferase assay reagent was added by the injector on the luminometer. The signal was measured using a 1 second delay followed by a 4 second measurement programme.
  • the IC 50 the
  • concentration of the drug required for reducing the replicon level by 50% in relation to the untreated cell control value can be calculated from the plot of the percentage reduction of the luciferase activity vs. drug concentration.
  • the clear plate was stained with 100 ⁇ 0.5% methylene blue in 50% ethanol at room temperature for lh, followed by solvation of the absorbed methylene blue in ⁇ per well of 1% lauroylsarcosine. Absorbance of the plate was measured on a microplate
  • concentration of drug required to reduce the total cell area by 50% relative to the DMSO controls can be calculated by plotting the absorbance at 620 nm minus background against drug concentration.
  • the compounds of Formula (I), and pharmaceutically acceptable salts thereof, as hereinbefore defined may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the Formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
  • the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
  • the compounds may also be administered as suppositories.
  • solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin,
  • diluents e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g. starches, arabic gums, gelatin,
  • methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • the compound of Formula (I), or pharamaceutically acceptable salt thereof, as hereinbefore defined will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg/m body area of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose.
  • a unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
  • Preferably a daily dose in the range of 1-50 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
  • the compounds of Formula (I) and their pharmaceutically acceptable salts as hereinbefore defined have activity as pharmaceuticals, in particular as antiviral agents and especially as agents for the treatment of Flaviviridae infections. More particularly, the compounds of Formula (I) and their pharmaceutically acceptable salts may be used in the treatment of hepatitis C virus infection.
  • the present invention provides a compound of Formula (I), or a
  • the present invention further provides a compound of Formula (I), or a
  • the present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined for use in the treatment or prophylaxis of hepatitis C virus infection.
  • the present invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use in the treatment or prophylaxis of hepatitis C virus.
  • the present invention provides a method of treating, or reducing the risk of, hepatitis C virus infection in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, HCV infection.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
  • the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of viral infections.
  • the invention further relates to combination therapies for the treatment of a viral infection, particularly infection by hepatitis C virus, wherein a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined or a pharmaceutical composition or formulation comprising a compound of Formula (I), is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents.
  • the compounds of the invention may be administered in conjunction with one or more further active ingredients that are selected from: (a) a HCV protease inhibitor, for example IDX-320, MK-5172, IDX-320, BMS-650032, ACH-2684, ACH-1625,BI-1335, TMC435350, MK7009, ITMN-191, BILN-2061, VX-950, BILN-2065, BMS-605339, VX-500 and SCH 503034;
  • a HCV protease inhibitor for example IDX-320, MK-5172, IDX-320, BMS-650032, ACH-2684, ACH-1625,BI-1335, TMC435350, MK7009, ITMN-191, BILN-2061, VX-950, BILN-2065, BMS-605339, VX-500 and SCH 503034;
  • HCV polymerase inhibitor for example ABT-333, ABT-072, IDX-184, ANA598, VX- 222, PSI-938, PSI-7977, R-7128, MK-0608, VCH759, PF-868554, GS9190, NM283, valopicitabine, PSI-6130, XTL-2125, NM-107, R7128 (R4048), GSK625433, R803, R-1626, BILB-1941, HCV-796, JTK-109 and JTK-003, benzimidazole derivatives, benzo- 1,2,4- thiadiazine derivatives, phenylalanine derivatives,;
  • a HCV polymerase inhibitor for example ABT-333, ABT-072, IDX-184, ANA598, VX- 222, PSI-938, PSI-7977, R-7128, MK-0608, VCH759, PF-868554, GS9190, NM283,
  • an immunomodulatory agent for example ⁇ -, ⁇ -, and ⁇ - interferons such as rIFN-a 2b, rIFN-a 2ba, consensus IFN-a (infergen), feron, reaferon, intermax a, rIFN- ⁇ , infergen + actimmune, IFN-omega with DUROS, albuferon, locteron, Rebif, Oral IFN-a, IFN-a 2b XL, AVI-005, pegylated-infergen, pegylated derivatized interferon-a compounds such as pegylated rIFN-a 2b, pegylated rIFN-a 2a, pegylated IFN- ⁇ , compounds that stimulate the synthesis of interferon in cells, interleukins, Toll like receptor (TLR) agonists, compounds that enhance the development of type 1 helper T cell response and thymosin;
  • TLR Toll like receptor
  • HCV NS5a inhibitor such as A-831 and A-689, PPI-461 or BMS-790052;
  • ribavirin for example ribavirin, ribavirin analogs such as rebetol, copegus and viramidine (taribavirin), amantadine, and telbivudine, inhibitors of internal ribosome entry, alpha-glucosidase 1 inhibitors such as MX-3253 (celgosivir) and UT-231B,
  • hepatoprotectants such as IDN- 6556, ME-3738, LB-84451 and MitoQ
  • broad-spectrum viral inhibitors such as IMPDH inhibitors (e.g., mycophenolic acid and derivatives thereof, and VX-497, VX-148, and/or VX-944); and
  • HCV other drugs for treating HCV
  • drugs for treating HCV such as zadaxin, nitazoxanide, BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA-971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, and Oglufanide.
  • one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor for use in the treatment of HCV infection.
  • a method for the treatment of HCV infection in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in combination with one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor.
  • a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in combination with one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor and in association with a pharmaceutically acceptable diluents or carrier.
  • a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in combination with one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor and in association with a pharmaceutically acceptable diluents or carrier for use in the treatment of HCV infection.
  • kits which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in combination with one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor.
  • kits which comprises (a) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in a first unit dosage form, (b) one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor in a second unit dosage form and (c) container means for containing said first and second dosage forms.
  • a kit which comprises (a) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in a first unit dosage form, (b) one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor in a second unit dosage form and (c) container means for containing said first and second dosage forms.
  • a therapeutic combination which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined and one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor.
  • a combination product which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined and one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in combination with an interferon, ribavirin and VX950 also known as Telaprevir, (lS,3aR,6aS)-2-[(2S)-2-[[(2S)-2- Cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl] amino] -3 ,3 -dimethylbutanoyl] -N-[( S)- 1 - (cyclopropylamino)-l ,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole- 1-carboxamide or (3S,3aS,6aR)-2-[(2S)-2-[[(2S)-2-cyclohexyl-2-(pyrazine-2- carbonylamino)
  • a method for the treatment of HCV infection in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in combination with an interferon, ribavirin and VX950.
  • a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in combination with one or more further active ingredients that are selected from an interferon, ribavirin and VX950 and in association with a pharmaceutically acceptable diluents or carrier.
  • a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in combination with an interferon, ribavirin and VX950 and in association with a pharmaceutically acceptable diluents or carrier for use in the treatment of HCV infection.
  • kits which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in combination with an interferon, ribavirin and VX950.
  • kits which comprises (a) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in a first unit dosage form, (b) an interferon, ribavirin and VX950 in a second unit dosage form and (c) container means for containing said first and second dosage forms.
  • a therapeutic combination which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined and an interferon, ribavirin and VX950.
  • a combination product which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined and an interferon, ribavirin and VX950.
  • interferon examples include PEGASYS (Peginterferon alfa-2a) and Peglntron (Peginterferon alfa-2b).
  • therapeutic combination as referred to in this description is intended to mean any combination of the specified pharmaceutical agents that produces a therapeutic effect upon administration.
  • combination product as referred to in this description is intended to mean any product that comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined and another specified pharmaceutical agent or agents and includes, but is not limited to, an individual pharmaceutical preparation comprising both a compound of Formula (I) and another specified pharmaceutical agent or agents (i.e.
  • kits of parts comprising pharmaceutical preparations of a compound of Formula (I) and another specified pharmaceutical agent or agents as individual or separate preparations, storage means for pharmaceutical preparations of a compound of Formula (I) and another specified pharmaceutical agent or agents as either individual or separate preparations and/or means for dispensing pharmaceutical preparations of a compound of Formula (I) and another specified pharmaceutical agent or agents as either individual or separate preparations, wherein the term "individual pharmaceutical preparation" or
  • individual preparations is intended to mean a single pharmaceutical preparation which comprises both a compound of Formula (I) and another specified pharmaceutical agent or agents and wherein the term "separate preparations” is intended to mean two or more different pharmaceutical preparations one of which comprises a compound of Formula (I) and the others of which each comprise another specified pharmaceutical agent.
  • a therapeutic combination or a combination product comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined and one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor, for use in the treatment of hepatitis C virus infection.
  • a therapeutic combination or a combination product comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined and an interferon, ribavirin and VX950, for use in the treatment of hepatitis C virus infection.
  • the present invention provides the use of a therapeutic combination or a combination product comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined and one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor, in the manufacture of a medicament for the treatment of hepatitis C virus infection.
  • a therapeutic combination or a combination product comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined and one or more further active ingredients that are selected from a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, an interferon, ribavirin and a HCV NS5a inhibitor, in the manufacture of a medicament for the treatment of hepatitis C virus infection.
  • the present invention provides the use of a therapeutic agent
  • temperatures are given in degrees Celsius (°C); unless stated otherwise, operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18 to 25°C;
  • chromatography means flash chromatography on silica gel
  • yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
  • NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane, determined at 250MHz, using perdeuterio dimethyl sulphoxide (d 6 -DMSO) as solvent, unless otherwise stated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; coupling constants, J, are reported in Hz;
  • Liquid Chromatograph Agilent 1200 series, with PDA detector, scan range 190-400nm.
  • Mass spectrometer Agilent MSD 6120 operating in electrospray ionisation mode with +ve/ - ve ion switching.
  • Liquid Chromatograph Agilent 1200 series, with PDA detector, scan range 190-400nm.
  • Mass spectrometer Agilent MSD 6120 operating in electrospray ionisation mode with +ve/ - ve ion switching.
  • Liquid Chromatograph Waters Acquity UPLC, with PDA detector, (scan range 190-400nm) and ELSD.
  • Mass spectrometer Waters SQD operating in electrospray ionisation mode with +ve/ -ve ion switching. LC Conditions
  • Liquid Chromatograph Agilent 1200 series, with PDA detector, scan range 190-400nm.
  • Mass spectrometer Agilent MSD 6120 operating in electrospray ionisation mode with +ve/-ve ion switching.
  • Liquid Chromatograph Waters 600 pump, W2700 Sample Manager, W996 PDA detector Mass spectrometer: Waters ZQ operating in electrospray ionisation mode.
  • a 60L-reactor was set under inert atmosphere and charged with 2-aminobenzoic acid (3.00kg, 21.90 mol) and dichloromethane (55 L). 4-Methoxybenzaldehyde (3.60 kg, 26.50 mol) and acetic acid (0.67 L) were added. The resulting suspension was heated to 40 °C. At a temperature of 37 °C a clear solution was obtained. After stirring at 40 °C for 30 min the solution was cooled to 5 °C and sodium triacetoxyhydroborate (9.83 kg, 46.0 mol) was added in portions (caution: addition is very exothermic, efficient cooling is necessary). After complete addition the reaction was warmed to room temperature and stirred at that temperature over night (16 h).
  • the resulting suspension was stirred at 50 °C for 10 min and then cooled to room temperature within 2 h.
  • the obtained solid was filtered off, washed with TBME (4 L) and dried at 40 °C / 20 mbar for 12 h.
  • the title compound was isolated as a white solid in 99 % yield (1.78 kg, 99a/a% purity).
  • a 60L-reactor was set under inert atmosphere and charged with 1 -(4-methoxybenzyl)- lHBenzo[d][l,3]oxazine-2,4-dione (2) (6.43 kg, 22.70 mol) and acetic acid (46 L).
  • glycine 4.02 kg, 53.50 mol
  • the mixture was heated to 92 °C within 3 h (caution: upon heating a strong gas evolution was observed). At a temperature of 90 °C a clear solution was obtained. The mixture was stirred at 92 °C for 24 h.
  • a 40L-reactor was set under inert atmosphere and charged with l-(4-methoxybenzyl)3,4- dihydro-lH-benzo[e][l,4]diazepine-2,5-dione (3) (2.10 kg, 7.1 mol), toluene (21 L) and N,Ndimethylaniline (2.69 L, 21.3 mol).
  • phosphoryl trichloride 660 mL, 7.2 mol
  • the obtained yellow suspension was heated to 110 °C and stirred at this temperature over night (16 h).
  • the mixture was cooled to 25 °C and slowly added into a solution of potassium carbonate (7 kg) in water (25 L) and ice (5 kg) with stirring. The pH of the mixture stayed >12 at all times.
  • the resulting biphasic mixture was transferred into a 100 L-separating vessel. The organic layer was separated and the aqueous layer was extracted with toluene (5 L). The combined organic layers were dried over sodium sulphate and the solvent was evaporated on a rotavap (50 °C). To the crude product, heptanes (3 L) was added and the resulting suspension was stirred at room temperature on a rotavap for 20 min. The solvent was decanted off and this procedure was repeated for a second time.
  • the isolated solid was combined with the product which had crystallized from the combined heptane solutions after storage over night.
  • the obtained solid was dissolved in ethyl acetate (5 L) on a rotavap (50 °C). After cooling to room temperature the solution was filtered through 2.5 kg of silica gel. The silica gel was washed with ethyl acetate (25 L) and the collected solution was evaporated to dryness under reduced pressure (50 °C). TBME (2 L) was added to the residue and the suspension was stirred at room temperature over night (16 h). The suspension was cooled to 0 °C and stirred for 2 h at that temperature.
  • a 50L-autoclave was loaded with 3-azido-5-chloro-l-(4-methoxy-benzyl)-l,3-dihydro- benzo[e][l,4]diazepin-2-one (5) (1.0 kg, 2.81 mol, 1.0 eq), di-tert-butyl dicarbonate (0.98 kg, 4.50 mol, 1.5 eq).
  • Dioxane (12 L) was added in order to dissolve all solids, platinum (IV) oxide (70 g, 7 wt%>) was added and autoclave was pressurized with hydrogen (10 bar). After lh, pressure was released and autoclave was again repressurised with hydrogen (lObar).
  • a 30L-reactor was set under inert atmosphere. Iodine (2.72 kg, 10.74 mol) was dissolved in toluene (19 L) and stirred until full dissolution (3-4h) at ambient temperature. A 63L-reactor was set under inert atmosphere. Toluene (8 L) was fed into the reactor followed by addition of sodium hydride (60%, 0.859 kg, 21.47 mol). The suspension was cooled to 0-5°C and a solution of 3,5-dichlorophenol (1.75 kg, 10.74 mol) in toluene (8.75 L) was added during 1.5h keeping the internal temperature ⁇ 10°C. After complete addition, the mixture was further stirred for 45 min.
  • a 30L-reactor was set under inert atmosphere and a scrubber was loaded with 4N
  • the filtrate was concentrated at 45 °C / 16 mbar.
  • the residue was partitioned between heptanes (20 L) and water (8 L). After phase separation, the organic phase was further washed with water (8 L) and brine (8 L). All aqueous phases were back extracted with heptanes (5 L). The organic phases were combined and dried over Na 2 S0 4 .
  • the filtrate was evaporated and the crude product was re-crystallized from heptanes (4 L, 60°C to 0°C).
  • the title compound (10b) was obtained as off- white solid in 85% yield (3.13kg, 99a/a%> purity).
  • Dry dioxane (1.5 L) was degassed by passing a flow of argon through the solvent for 30 min.
  • CataCXiumPOMeCy (45.9 g, 124 mmol) and Pd(OAc) 2 (13.95 g, 62.2 mmol) were added and the mixture was stirred for 45 min to give a bright orange solution.
  • a 30L-reactor was set under inert atmosphere and charged with l ,5-dichloro-3-ethoxy-2-iodobenzene (10b) (1.97 kg, 6.22 mol) in dioxane (18 L).
  • Triethylamine (2.58 L, 18.6 mol) was added and the mixture was cooled to 10°C.
  • the mixture was degassed by passing a flow of argon through the solution for 1 h.
  • 4-4,5, 5-tetramethyl-l ,3,2-dioxaborolane (1.35 kg, 10.6 mol) was rapidly added. Some gas evolution but no significant exotherm could be observed.
  • a flow of argon was again passed through the solution for 10 min.
  • the clear yellow solution formed was heated to 80°C (internal temperature) and the catalyst solution was added via cannula within 10 min. The reaction was kept at this temperature for 5 h before cooling to ambient.
  • the mixture was concentrated at 45 °C / 20 mbar and the residue was re-dissolved in DCM (12 L).
  • the mixture was filtered over a plug of Hyflo (1 kg).
  • a 30L-glass reactor was set under inert atmosphere. 1, 2 -dimethoxy ethane (15 L) and 2N Na 2 C0 3 -solution (7 L, 14.0 mol, 3.1 eq) were added. 2-(2,4-dichloro-6-ethoxyphenyl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (lib) (1.59 kg, 5.0 mol, 1.1 eq) and [5-chloro-l-(4- methoxy-benzyl)-2-oxo-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl]-carbamic acid tert-butyl ester (6) (1.96 kg, 4.56 mol, 1.0 eq) were dissolved in the mixture.
  • Example 7 2-(2-(Cyclopropylamino)-2-oxoethoxy)-5-fluoro-N-(2-oxo-5-(2,4,6- trichlorophenyl)-2,3-dihydro-lH-benzo[e] [l,4]diazepin-3-yl)nicotinamide
  • the free base (14.1 g, approx 5% dioxane) was suspended in isopropylacetate (220 mL) and (-)-2,3-dibenzoyl-L-tartaric acid (11.28 g, 31.5 mmol) and 3,5- dichlorosalicylaldehyde (0.30 g, 1.6 mmol) were added.
  • the yellow suspension was heated to 70°C for 3h.
  • the thick suspension was cooled to rt overnight.
  • the solid was filtered off and rinsed with iPrOAc (lOOmL).
  • the colourless solid was dried at hgh vacuum for 2h.
  • the solid was partitioned between TBME/1N NaOH (300mL, 1 : 1).

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Abstract

La présente invention concerne des dérivés de benzodiazépine de formule (I) dans laquelle X, L1, L2, R1, R2, R3, R4, R5, R6, R7, R8 et R9 sont tels que définis dans la description. La présente invention a également pour objet des procédés de préparation de ces composés, de compositions pharmaceutiques les contenant et leur utilisation dans le traitement ou la prophylaxie d'une infection par le virus de l'hépatite C.
PCT/GB2011/051048 2010-06-03 2011-06-03 Composés de benzodiazépine utiles pour le traitement de l'hépatite c Ceased WO2011151652A1 (fr)

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
WO2013030750A1 (fr) 2011-09-01 2013-03-07 Lupin Limited Composés antiviraux
WO2013118102A1 (fr) 2012-02-10 2013-08-15 Lupin Limited Composés antiviraux avec une fraction hétérotricycle
CN109776437A (zh) * 2019-01-21 2019-05-21 江苏中旗科技股份有限公司 一种新的甲磺草胺的制备方法
US11247973B2 (en) * 2016-08-15 2022-02-15 The University Of Durham Antiviral benzodiazepine compounds
US11634425B2 (en) 2019-08-20 2023-04-25 Pfizer Inc. Pharmaceutical compounds
WO2025070390A1 (fr) * 2023-09-25 2025-04-03 第一三共株式会社 Procédé de production d'un composé de n-pyridylsulfonamide, d'un composé de pyridine et d'un cristal de composé de n-pyridylsulfonamide
US12384764B2 (en) 2019-11-01 2025-08-12 Pfizer Inc. Pharmaceutical compounds

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013030750A1 (fr) 2011-09-01 2013-03-07 Lupin Limited Composés antiviraux
WO2013118102A1 (fr) 2012-02-10 2013-08-15 Lupin Limited Composés antiviraux avec une fraction hétérotricycle
WO2013118097A1 (fr) 2012-02-10 2013-08-15 Lupin Limited Composés antiviraux avec une fraction dibenzooxahétérocycle
US9073942B2 (en) 2012-02-10 2015-07-07 Lupin Limited Antiviral compounds with a heterotricycle moiety
US9073943B2 (en) 2012-02-10 2015-07-07 Lupin Limited Antiviral compounds with a dibenzooxaheterocycle moiety
US11247973B2 (en) * 2016-08-15 2022-02-15 The University Of Durham Antiviral benzodiazepine compounds
CN109776437A (zh) * 2019-01-21 2019-05-21 江苏中旗科技股份有限公司 一种新的甲磺草胺的制备方法
CN109776437B (zh) * 2019-01-21 2022-02-25 江苏中旗科技股份有限公司 一种甲磺草胺的制备方法
US11634425B2 (en) 2019-08-20 2023-04-25 Pfizer Inc. Pharmaceutical compounds
US12227507B2 (en) 2019-08-20 2025-02-18 Pfizer Inc. Pharmaceutical compounds
US12384764B2 (en) 2019-11-01 2025-08-12 Pfizer Inc. Pharmaceutical compounds
WO2025070390A1 (fr) * 2023-09-25 2025-04-03 第一三共株式会社 Procédé de production d'un composé de n-pyridylsulfonamide, d'un composé de pyridine et d'un cristal de composé de n-pyridylsulfonamide

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